MDA 2023: No new cardiac, liver findings seen with Skyclarys in MOXIe trial

MDA conference posters detail changes in key markers seen in MOXIe trial

by Lindsey Shapiro, PhD | March 21, 2023

Skyclarys (omaveloxolone), the first approved therapy for Friedreich's ataxia (FA), demonstrate a favorable heart and liver safety profile in the MOXIe clinical trial, analyses of trial data report.

Changes in markers of heart or liver function generally were not accompanied by changes in disease symptoms.

Skyclarys "was well tolerated and had a manageable … safety profile in clinical trials," the researchers wrote.

Safety findings were detailed in a pair of posters presented at the Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, being held March 19-22.

Skyclarys, by Reata Pharmaceuticals, was approved to treat FA in the United States last month. Taken orally, it works to improve the health of mitochondria, the cells’ energy production centers.

The U.S. Food and Drug Administration gave Skyclarys the green light for patients starting at age 16 based on findings from the two-part, Phase 2 MOXIe trial (NCT02255435), conducted at sites in the U.S., Europe, and Australia.

After a first, dose-finding phase, the trial's second part evaluated the safety and efficacy of Skyclarys, at 150 mg daily, against a placebo for nearly one year.

Top-line study results showed the treatment led to significant gains in neurological function relative to placebo, with benefits generally sustained for up to three years in the trial's open-label extension phase.

Skyclarys was found to be generally safe and well tolerated. Based on trial data, however, certain changes in markers of heart and liver function are noted on the therapy's prescribing label.

These cardiac and liver findings were described in more detail at the MDA conference, beginning with the poster, "Assessment of Cardiac Safety in Patients with Friedreich's Ataxia in the MOXIe Trial of Omaveloxolone."

Cardiomyopathy, a disease of the heart's muscle that makes it harder to pump blood, occurs in about two-thirds of FA patients.

A total of 40 MOXIe trial participants — 25 assigned Skyclarys and 15 to placebo — had mild-to-moderate cardiomyopathy, among the 103 patients enrolled in part two.

Trial data indicated that cardiovascular events were not more frequent among those receiving Skyclarys (9.8%) compared with placebo (13.5%) across this overall trial phase.

Within the subgroup of patients with cardiomyopathy, rates also were similar between Skyclarys (12%) and placebo (13.3%) groups.

Serious cardiac events were reported in three Skyclarys group patients and one on placebo, including atrial fibrillation, an irregular and rapid heartbeat, seen in one patient in both these groups.

No differences were observed between the groups in terms of heart rate, blood pressure, or other measures of heart function.

Skyclarys-treated patients, but not those on placebo, saw slight increases in blood levels of B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP), both of which can be markers of heart failure. No signs of fluid retention, which can indicate heart failure, were observed.

Skyclarys’ use also led to temporary changes in blood cholesterol, which returned to near normal after treatment stopped.

As of March 24, 2022, covering up to 4.3 years of Skyclarys treatment across MOXie and its extension phase, no new cardiac signals had been identified, the researchers reported.

Liver-related findings were discussed in the poster, "Assessment of Hepatic Safety in Patients with Friedreich's Ataxia in the MOXIe Trial of Omaveloxolone."

Hepatobiliary disorders, those affecting the liver, pancreas or gallbladder, occurred at similar rates in people given Skyclarys (two patients) or placebo (one patient).

Increases in certain liver enzymes were observed more often in the Skyclarys group.

Specifically, elevated levels of both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were seen in 1.9% of the placebo patients. In comparison, 37.2% of people given Skyclarys had elevated ALT levels, and 21.6% had higher AST levels. One person randomized to Skyclarys stopped treatment due to ALT/AST elevations.

These enzyme increases were considered mild-to-moderate and usually occurred in the first 12 weeks after starting treatment. Levels dropped once the treatment was stopped.

Gamma-glutamyl transferase (GGT) levels also increased in 5.9% of those on Skyclarys and no placebo patients.

Overall, these changes were "consistent with the pharmacologic activity of [Skyclarys]," according to the researchers.

As of the March 24 data cutoff date, no new safety signals were observed. Across the trial, most side effects were mild or moderate.

The possibility of changes in BNP, cholesterol, and liver enzymes are noted in Skyclarys’ prescribing label, with recommendations to monitor these markers during the start of treatment, and/or periodically throughout the therapy's use.